The present invention relates to the use of tapentadol in the (i) treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety, and/or in the (ii) treatment or the inhibition of depression and/or of anxiety.
Tapentadol (CG5503), the chemical name for which is (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is a synthetic, centrally-acting analgesic that is effective for the treatment of moderate to moderately-severe acute or chronic pain. The compound can be employed as the free base or its physiologically acceptable salts and solvates. Preparation of the free base is known e.g. from U.S. Pat. No. 6,248,737 (=EP 693,475).
Tapentadol is a centrally acting analgesic with a dual mode of action consisting of μ-opioid receptor (MOR) agonism and norepinephrine (NE) reuptake inhibition. The efficacy, safety, and pharmacokinetic profile of tapentadol indicate that the drug is useful in treating acute as well as chronic pain.
Subjects suffering from pain often fall into depression and anxiety, especially if the pain is chronic or neuropathic. In patients with chronic or neuropathic pain 8 to 50% have been reported to have current major depression (Smith G R, The epidemiology and treatment of depression when it co-exists with somatoform disorders, somatization or pain. Gen Hosp Psychiatry 1992, 14: 265-276). In another analysis of 1,016 patients, the prevalence of depression was 12% in individuals with 3 or more pain complaints (Dworkin S F et al., Multiple pains and psychiatric disturbance: an epidemiological investigation. Arch Gen Psychiatry 1990, 47: 239-244).
The most serious consequences of major depression are suicide and increased rates of suicidal ideation and suicide completion have been reported by patients suffering from chronic pain conditions (Magni et al., Suicidality in chronic abdominal pain; an analysis of the Hispanic Health and Nutrition Examination Survey (HHANES). Pain 1998, 76: 137-144). Oncology patients with concomitant pain and depression were significantly more likely to request assistance in committing suicide as well as actively taking steps to commit suicide. In contrast those with pain in the absence of depression were unlikely to request the intervention of euthanasia and physician-assisted suicide (Emmanuel et al., Euthanasia and physician assisted suicide; attitudes and experiences of oncology patients, oncologists and the public. Lancet 1996, 347: 1810).
On the other hand, subjects suffering from depression and/or anxiety often have pain symptoms, which can be attributed to a somatoform disorder (psychogenic pain). The pain symptoms are physical symptoms, which typically do not have an identifiable physical origin. Instead, they are the result of internal psychological conflicts that are unconsciously expressed as physical signs.
It is evident that subjects suffering from depression and/or anxiety induced by pain or inducing pain symptoms are in need of medicaments for the treatment of both, the depression and/or anxiety as well as the pain.
US 2009/0215809 discloses pharmaceutical compositions comprising a crystalline prodrug of an antiepileptic drug, namely pregabalin ((S)-3-(Aminomethyl)-5-methylhexanoic acid) for the treatment of certain diseases and disorders, including, for example, neuropathic pain, generalized anxiety disorder, fibromyalgia, migraine, hot flashes, restless legs syndrome, and sleep disorders. The pharmaceutical composition may additionally comprise an opioid agonist selected from tramadol, tapentadol, and oxycodone as a second therapeutic agent.
Similarly, U.S. Pat. No. 7,868,043 discloses pharmaceutical compositions comprising a mesophasic pregabalin prodrug and methods of use thereof.
US 2010/0297181 discloses methods for treating epilepsy, mental disorders and/or deficits in sensory organ by administering to patients therapeutically effective amounts of AMPA receptor antagonists, i.e. antiepileptic drugs, in combination with one or more other active ingredients useful for treating epilepsy, mental disorders and/or deficits in the sensory organ. Tapentadol is mentioned in a list of suitable active ingredients to be administered in combination with AMPA receptor antagonists. As mental disorders, mood disorders, such as depressions, are listed.
The use of antiepileptic drugs, however, can be detrimental because it has been found that it can be associated with a significantly increased risk for suicide-related events in patients with depression (Arana et al., Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010, 363: 542-551). Furthermore, a pharmaceutical composition comprising a combination of an antiepileptic and tapentadol can be disadvantageous because of adverse events caused by each drug itself and due to interactions of the drugs with each other, respectively.
Accordingly, there is a need for pharmaceutical compositions comprising a single pharmacologically active ingredient for use in the treatment of pain in a subject suffering from depression and/or anxiety, and/or for use in the treatment or the inhibition of depression and/or anxiety, wherein the single pharmacologically active ingredient may simultaneously or sequentially act as an antidepressant and as an analgesic.
US 2009/0306050 discloses compounds, such as lofepramine, exhibiting an activity as a potent norepinephrine (NE) reuptake inhibitor, and an activity at the dopamine D2 receptor sites. It was found that these special compounds are effective in the treatment and inhibition of various diseases and disorders associated with norepinephrine reuptake, such as pain predominant-type depression and depression secondary to chronic or neuropathic pain. However, antidepressants such as lofepramine exhibit several nuisance side effects and several warnings have been reported.
M. Afilalo et al., Clin. Drug Investig. 2010, 30(8), 489-505 discloses information concerning the efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee.
B. Kupferwasser et al., Osteoarthritis and Cartilage 2009, Vol. 17, Supplement 1, 179 discloses an evaluation of long-term treatment with tapentadol extended release and oxycodone controlled release in patients with chronic low back or osteoarthritis pain.
R. Lange et al., Osteoarthritis and Cartilage 2010, Vol. 18, Supplement 2, 147-148 discloses results from randomized, double-blind phase 3 studies of tapentadol prolonged release in patients with moderate to severe chronic nociceptive and neuropathic pain.
B. Kupferwasser et al., Osteoarthritis and Cartilage 2010, Vol. 18, Supplement 2, 149 discloses information concerning the health status of patients who received tapentadol prolonged release during an open-label extension study.
S. Schwartz et al., Current Medical Research & Opinion, 27(1), 2011, 151-162 discloses results of a randomized-withdrawal, placebo-controlled trial concerning safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy.
Accordingly, there remains a need for improved pharmaceutical compositions comprising a single pharmacologically active ingredient useful for treating pain and simultaneously or sequentially treating depression and/or anxiety.